Absence of Bcl-XL down-regulation in response to cisplatin is associated with chemoresistance in ovarian carcinoma cells

Objective. Recurrence and subsequent acquired chemoresistance to platinum-based treatments constitute major hurdles to ovarian carcinoma therapy. Our objective was to examine the involvement of Bcl-X-L anti-apoptotic protein in resistance to cisplatin. Methods. We described the effect of cisplatin on cell cycle and apoptosis induction in sensitive (IGROV1 and OAW42) and resistant (IGROV1-R10 and SKOV3) ovarian carcinoma cell lines. We correlated it with Bcl-X-L mRNA and protein expression after exposure to cisplatin. We then used bcl-x(S) gene transfer to impede Bcl-X-L activity. Results. Our study showed that Bcl-X-L basal expression was high in both sensitive and resistant cell lines, as well as in all the studied ovarian tumor samples. Thus, Bcl-X-L basal expression could not allow to predict sensitivity. Wondering whether variation of Bcl-X-L, level in response to cisplatin could be a better determinant of sensitivity, we investigated the expression of this protein in the cell lines after treatment. Cisplatin-induced down-regulation of Bcl-X-L was strictly associated with apoptosis and absence of recurrence in vitro. Conversely, the maintenance of Bcl-X-L expression in response to cisplatin appeared as a sine qua non condition to escape to treatment. To try to sensitize SKOV3 cells by impeding anti-apoptotic activity of Bcl-X-L, we transfected bcl-x(S) gene in these cells. Bcl-x(S) exogenous expression was only slightly cytotoxic on its own, but highly sensitized SKOV3 resistant cells to cisplatin-induced apoptosis, and delayed recurrence. Conclusion. This work thus provides one more argument to put Bcl-X-L forward as a pertinent target of inhibition to overcome chemoresistance of epithelial ovarian carcirioma. (c) 2006 Elsevier Inc. All rights reserved.